Vijayaragavan Muralidharan

Aneurysms of the splenic artery – A review

Splenic artery aneurysm is the third most common intra-abdominal aneurysm with a prevalence as high as 10% in some studies. Widespread use of abdominal imaging has resulted in the increasing detection of asymptomatic incidental aneurysms. In this manuscript we review the changing incidence, risk factors and evolving therapeutic options in the era of minimally invasive therapy and have developed a treatment algorithm for practical use. Aneurysms with a low risk of rupture may be treated conservatively but require regular imaging to ascertain progress. Available evidence suggests that splenic artery aneurysms that are symptomatic, enlarging, more than 2 cm in diameter or those detected in pregnancy, childbearing age or following liver transplantation are at high risk of rupture and should undergo active treatment. Prophylactic screening should be reserved for those with multiple risk factors, such as pregnancy in liver transplant recipients. All false aneurysms should also be treated. The primary therapeutic approach should be endovascular therapy by either embolization or stent grafting.

Effect of ACE inhibitors and angiotensin II receptor antagonists in a mouse model of colorectal cancer liver metastases

Background and Aims:  Angiotensin converting enzyme inhibitors (ACE‐I) and angiotensin II type I receptor (AT1R) antagonists are commonly used as a treatment for hypertension. Recent experimental and population studies have suggested that these agents may exert an inhibitory effect on malignancy, possibly through anti‐angiogenic pathways. The aim of this study was to investigate the effect of an ACE‐I (captopril) and an AT1R antagonist (irbesartan) in colorectal cancer liver metastases.

Long-term survival of patients with unresectable colorectal liver metastases treated by percutaneous interstitial laser thermotherapy

In situ ablation of colorectal cancer (CRC) liver metastases is an accepted form of treatment for selected patients. It is associated with low morbidity and mortality and increases the number of patients who may benefit from therapy compared to resection alone. This study assesses the impact of interstitial laser thermotherapy (ILT) on local tumor control and long-term survival in patients with unresectable CRC liver metastases. Percutaneous ILT was performed in patients with unresectable CRC liver metastases between January 1992 and December 1999 using a bare-tip quartz fiber connected to an Nd:YAG laser source. This was prior to the routine use of a diffusing fiber for ablative therapy. Treatment was monitored with real-time ultrasonography. Tumors were considered unresectable based on their anatomic location or the extent of liver involvement. Patients with extrahepatic disease, more than five liver metastases, or tumors larger than 10 cm in diameter were excluded from this study. Local tumor control was assessed by dynamic computed tomography (CT) 6 months after therapy. Long-term follow-up was undertaken, and the impact of various factors on survival was analyzed. Eighty patients with a mean age of 63.8 years were suitable for ILT. In total, 168 liver tumors with a median diameter of 5 cm (range 1–10 cm) were so treated. There were no procedure-related deaths. The overall complication rate was 16%, with all cases managed conservatively. Bradycardia (n = 5), pneumothorax (n = 3), and persistent pyrexia (n = 3) were the most common complications. Complete tumor ablation was noted in 67% of patients assessed by CT 6 months following the initial therapy. Median follow-up was 35 months (range 4–96 months), with 10 patients alive at the end of this period. Altogether there were 67 deaths, which were related to hepatic disease in 55 cases and to extrahepatic disease in 9; they were unrelated to malignancy in 3 others. Three patients were excluded from follow-up after ILT down-staging of tumors that allowed complete surgical resection. The median disease-free survival of patients treated by ILT was 24.6 months, with a 5-year survival of 3.8%. Poor tumor differentiation and the presence of more than two hepatic metastases were associated with lower overall survival (p < 0.01). Fourteen patients treated by ILT for postoperative hepatic recurrences had the best outcome, with a median overall survival of 36.3 months and a 5-year survival of 17.2%. Percutaneous ILT is a minimally invasive, safe, effective technique that appears to improve overall survival in specific patients with unresectable CRC liver metastases, compared to the natural history of untreated disease reported in the literature.

Interstitial laser thermotherapy in the treatment of colorectal liver metastases.

Metastatic liver disease is the commonest cause of death in patients with colorectal cancer. A small proportion of these patients (10%) may be treated by surgical resection with five year survival approaching 35–40%.Alternative treatment modalities for localised hepatic disease include in situ ablative techniques that have the advantages of percutaneous application and minimal morbidity. These include Interstitial Laser Thermotherapy (ILT), Radio Frequency Ablation, Percutaneous Microwave therapy, and Focussed Ultrasound Therapy. This article focuses specifically on the development and utilisation of ILT in the treatment of colorectal liver metastases. It provides a review of the pathophysiological factors involved, present status of clinical studies, and future directions. ILT is a safe technique for the treatment of colorectal liver metastases. It may be delivered by minimally invasive techniques to lesions considered unresectable by present criteria. Limitations include the extent and completeness of tumour necrosis achieved as well as imaging techniques. Clinical problems include a lack of controlled studies. Assessment of long‐term survival in prospective randomised trials is needed to assess the efficacy of this procedure. J. Surg. Oncol. 2001;76:73–81.

Specialist Early and Immediate Repair of Post-laparoscopic Cholecystectomy Bile Duct Injuries Is Associated With an Improved Long-term Outcome

Introduction:A majority of bile duct injuries (BDI) sustained during laparoscopic cholecystectomy require formal surgical reconstruction, and traditionally this repair is performed late. We aimed to assess long-term outcomes after repair, focusing on our preferred early approach. Methods:A total of 200 BDI patients [age 54(20–83); 64 male], followed up for median 60 (5–212) months were assessed for morbidity. Factors contributing to this were analyzed with a univariate and multivariate analysis. Results:A total of 112 (56%) patients were repaired by specialist hepatobiliary surgeons [timing of repair: immediate, n = 28; early (<21 days), n = 43; and late (>21 days) n = 41], whereas 45 (22%) underwent repair by nonspecialist surgeons before specialist referral [immediate, n = 16; early, n = 26 and late, n = 03]. Outcomes after immediate and early repairs were comparable to late repairs when performed by specialists [recurrent cholangitis:11%, 12%, and 10%; P = 0.96, NS; re-stricture:18%,5%, and 29%; P = 0.01; nonsurgical intervention: 14%, 5%, and 24%; P<0.03; redo surgery: 4%, 2%, and 5%; P = 0.81, NS; overall morbidity: 21%, 14%, and 39%; P<0.02]. On multivariate analysis, immediate and early repairs done by nonspecialist surgeons were independent risk factors (P < 0.05) for recurrent cholangitis [50% and 27%], re-stricturing (75% and 61%), redo reconstructions (31% and 61%), and overall morbidity (75% and 84%). Conclusion:Immediate and early repair after BDI results in comparable, if not better long-term outcomes compared to late repair when performed by specialists.

In vitro and in vivo evaluation of tumor targeting styrene-maleic acid copolymer-pirarubicin micelles: Survival improvement and inhibition of liver metastases

Pirarubicin is a derivative of doxorubicin with improved intracellular uptake and reduced cardiotoxicity. We have prepared a micellar formulation of pirarubicin using styrene‐maleic acid copolymer (SMA) of mean molecular weight of 1.2 kDa, which exhibits a mean diameter of 248 nm in solution. Being a macromolecule, SMA‐pirarubicin micelles exhibit excellent tumor targeting capacity due to the enhanced permeability and retention (EPR) effect. Here we report the antitumor activity of SMA‐pirarubicin micelles on human colon and breast cancer cell lines in vitro, and a murine liver metastasis model in vivo. Metastatic tumor microvasculature, necrosis, apoptosis, proliferation, and survival were also investigated using immunohistochemistry for Ki‐67, active caspase‐3, and CD34, respectively. Drug cytotoxicity in vitro was assessed using MTT (3‐[4,5‐dimethyl‐2‐thiazolyl]‐2, 5‐diphenyl‐2H‐tetrazolium bromide) assay. In vivo, SMA‐pirarubicin was administered at 100, 150, or 200 mg/kg (pirarubicin equivalent). Tumor microvasculature was also assessed using scanning electron microscopy. Styrene‐maleic acid copolymer (SMA)‐pirarubicin micelles were toxic against human colorectal and breast cancer cells in vitro. IC50 was at or below 1 μM, free pirarubicin equivalent. In vivo, SMA‐pirarubicin at 100 mg/kg reduced tumor volume by 80% and achieved a survival rate of 93% at 40 days after tumor inoculation. Styrene‐maleic acid copolymer (SMA)‐pirarubicin micelles demonstrated potent antitumor activity in this liver metastases model, contributing to prolonged survival. Histological examination of tumor nodules showed significant reduction and proliferation of tumor cells (>90%). The present results suggest that investigation of the effect of multiple dosing at later time points to further improve survival is warranted. (Cancer Sci 2010)

Liver transplant recipient selection: MELD vs. clinical judgment

Minimization of death while waiting for liver transplantation involves accurate prioritization according to clinical status and appropriate allocation of donor livers. Clinical judgment in the Liver Transplant Unit Victoria (LTUV) was compared with Model for End‐Stage Liver Disease (MELD) in a retrospective analysis of the LTUV database over the 2‐year period August 1, 2002, through July 31, 2004. A total of 1,118 prioritization decisions occurred. Decisions were concordant in 758 (68%), comparing priorities assigned by clinical judgment with those assigned by MELD, P < 0.01. A total of 263 allocation decisions occurred. Decisions were concordant in 190 (72%) and 203 (77%) of the cases, comparing donor liver allocation with prioritization by MELD and clinical judgment, respectively. Of the 52 patients allocated a liver, only 23 would have been allocated on the basis of MELD while 29 had been prioritized on the waiting list in the week prior to transplantation. A total of 10 patients died on the waiting list in the 2‐year period (annual adult waiting list mortality is 9.3%). Patients who subsequently died waiting were 3 times as likely to be prioritized by MELD as clinical judgment (29% vs. 9%, respectively). One half (3 of 6) of the patients who could have received a donor liver but who died waiting would have been allocated the organ on the basis of MELD. In conclusion, an allocation process based on MELD rather than clinical judgment would significantly alter organ allocation in Australia and may reduce waiting list mortality. (Liver Transpl 2005;11:621–626.)

Risk factors for liver transplantation waiting list mortality

Background and Aim:  The gap between the demand for liver transplantation and organ donation rates has a major impact on waiting list mortality. Understanding the risk factors that predict liver transplant waiting list death may help optimize organ allocation policy and reduce waiting list deaths.

Styrene maleic acid-pirarubicin disrupts tumor microcirculation and enhances the permeability of colorectal liver metastases.

Background: Doxorubicin is a commonly used chemotherapy limited by cardiotoxicity. Pirarubicin, derived from doxorubicin, selectively targets tumors when encapsulated in styrene maleic acid (SMA), forming the macromolecular SMA pirarubicin. Selective targeting is achieved because of the enhanced permeability and retention (EPR) effect. SMA-pirarubicin inhibits the growth of colorectal liver metastases, but tumor destruction is incomplete. The role played by the tumor microcirculation is uncertain. This study investigates the pattern of microcirculatory changes following SMA-pirarubicin treatment. Methods: Liver metastases were induced in CBA mice using a murine-derived colon cancer line. SMA-pirarubicin (100 mg/kg total dose) was administered intravenously in 3 separate doses. Twenty-four hours after chemotherapy, the tumor microvasculature was examined using CD34 immunohistochemistry and scanning electron microscopy. Tumor perfusion and permeability were assessed using confocal in vivo microscopy and the Evans blue method. Results: SMA-pirarubicin reduced the microvascular index by 40%. Vascular occlusion and necrosis were extensive following treatment. Viable cells were arranged around tumor vessels. Tumor permeability was also increased. Conclusion: SMA-pirarubicin damages tumor cells and the tumor microvasculature and enhances tumor vessel permeability. However, tumor necrosis is incomplete, and the growth of residual cells is sustained by a microvascular network. Combined therapy with a vascular targeting agent may affect residual cells, allowing more extensive destruction of tumors.

Outcomes of contemporary management of gangrenous and non-gangrenous acute cholecystitis.

BACKGROUND Gangrenous cholecystitis (GC) is considered a more severe form of acute cholecystitis. The risk factors associated with this condition and its impact on morbidity and mortality compared with those of non-gangrenous acute cholecystitis (NGAC) are poorly defined and based largely on findings from older studies. METHODS Patients with histologically confirmed acute cholecystitis treated in specialized units in a tertiary hospital between 2005 and 2010 were identified from a prospectively maintained database. Data were reviewed retrospectively and patients with GC were compared with those with NGAC. RESULTS A total of 184 patients with NGAC and 106 with GC were identified. The risk factors associated with GC included older age (69 years vs. 57 years; P= 0.001), diabetes (19% vs. 10%; P= 0.049), temperature of >38 °C (36% vs. 16%; P < 0.001), tachycardia (31% vs. 15%; P= 0.002), detection of muscle rigidity on examination (27% vs. 12%; P= 0.01) and greater elevations in white cell count (WCC) (13.4 × 10⁹/l vs. 10.7 × 10⁹/l; P < 0.001), C-reactive protein (CRP) (94 mg/l vs. 17 mg/l; P= 0.001), bilirubin (19 µmol/l vs. 17 µmol/l; P= 0.029), urea (5.3 mmol/l vs. 4.7 mmol/l; P= 0.016) and creatinine (82 µmol/l vs. 74 µmol/l; P= 0.001). The time from admission to operation in days was greater in the GC group (median = 1 day, range: 0-14 days vs. median = 1 day, range: 0-10 days; P= 0.029). There was no overall difference in complication rates between the GC and NGAC groups (22% vs. 14%; P= 0.102). There was a lower incidence of common bile duct stones in the GC group (5% vs. 13%; P= 0.017). Gangrenous cholecystitis was associated with increased mortality (4% vs. 0%; P= 0.017), but this was not an independent risk factor on multivariate analysis. CONCLUSIONS Gangrenous cholecystitis has certain clinical features and associated laboratory findings that may help to differentiate it from NGAC. It is not associated with an overall increase in complications when treated in a specialized unit.